Protein-protein interactions underlying molecular recognition are studied, utilizing monoclonal antibodies (MAbs) specific for the protein hen egg white lysozyme (HEL), a protein which has long served as a prototype for investigating the specificity of immune recognition. The X-ray structure of HyHEL-5 Fab complexed with a single site-directed mutant of HEL, R68K which reduces the affinity of the complex by a factor of over 103, has been solved and refined; these results represent the first time structures have been obtained for 2 antigens, differing at only a single critical residue, complexed to the same antibody, and will provide valuable insight about role of Arginine side chains in protein-protein interactions. We are beginning to define fundamental principles that will allow prediction of function from structure, principles that are critical to such applications as antibody design and vaccine development. We are also approaching the problem of vaccine development by examining structurally constrained peptides as possible immunogens for both B-cells and T-cells, and by investigating immunogenicity and protective epitopes in Shigella flexnerii. Experiments are in progress to examine the role of circulating antibody- antigen complexes in determinant selection by B-cells and T-cells. Experiments with specific-pathogen-free and conventional BALB/c mice suggest a significant influence of antigenic exposure, particularly viral antigens, on development of the specificity repertoire and plasmacytomagenesis.